SGK1 is a regulator of islet beta cell mass and secretory function

SGK1 是胰岛 β 细胞质量和分泌功能的调节剂

• 批准号: 10608945
• 负责人: James Jason Collier
• 金额: $ 37万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608945
• 关键词: Address; Anabolism; Automobile Driving; Beta Cell; Biochemical Pathway; Biological Assay; Calcium; Cell Cycle; Cell Proliferation; Cells; Collaborations; Coupling; Cues; Data; Development; Diabetes Mellitus; Diagnosis; Electrophysiology (science); Event; Exposure to; Fatty acid glycerol esters; Future; Gene Expression; Generations; Genes; Genetic; Glucocorticoids; Glucose; Goals; Growth; Health; Health Care Costs; Healthcare Systems; Human; Image; In Vitro; Infusion procedures; Insulin; Insulin Resistance; Link; Lipids; Mediating; Metabolic; Metabolic Diseases; Molecular; Mus; Nutrient; Nutritional; Obesity; Outcome; Oxygen Consumption; Pathway interactions; Pentosephosphates; Phosphotransferases; Population; Prediabetes syndrome; Prevalence; Process; Proliferating; Publishing; Purines; Pyrimidine; Regulation; Rodent; Serum; Signal Induction; Signal Transduction; Solid; Source; Stimulus; Structure of beta Cell of islet; Techniques; Testing; Tracer; United States; cell growth; cellular targeting; cytokine; design; detection of nutrient; feeding; gene network; glucose tolerance; improved; in vivo; insight; insulin secretion; islet; metabolomics; mouse model; novel; oxidation; response; sensor; stable isotope; stem cells; therapy design; transcriptome sequencing; translational impact

Pancreatic beta-cell mass expansion occurs in the early stages of obesity and insulin resistance. Conversely, humans with diabetes have reduced numbers and diminished function of pancreatic beta-cells, indicating that islet beta-cell expansion and loss are dynamic processes subject to signal-induced regulation. Using external cues that signal demand for insulin, or that produce insulin resistance, we queried changes in gene expression in rodent and human beta-cells for inducible genes linked with growth and proliferation pathways. This approach yielded the serum and glucocorticoid inducible kinase 1 (SGK1), which is rapidly upregulated after exposure to cytokines, glucose, glucocorticoids, and lipids. Thus, we created mice lacking SGK1 in pancreatic beta-cells to address the fundamentally important question: does inhibition of SGK1 in islet beta-cells block their ability to expand during states of caloric overload and insulin resistance? Our preliminary data shows that SGK1 deletion in beta-cells restricts islet mass expansion during high-fat feeding. Intriguingly, SGK1 inhibition in beta-cells augmented insulin secretion in vitro and in vivo, resulting in improved whole-body glucose tolerance. Based on these preliminary data, we hypothesize that restricting beta-cell proliferation has the added benefit of improving stimulus-secretion coupling to promote insulin secretion. To test this overarching hypothesis, the following aims are proposed. Specific Aim 1 will investigate how SGK1 regulates beta-cell mass in response to signals that create a demand for insulin. Using in vivo approaches that build on our preliminary data using mice with beta- cell deletion of SGK1, we will investigate the early changes in beta-cell proliferation using two established experimental paradigms: high-fat feeding and continuous glucose infusion. Specific Aim 2 will investigate the mechanisms underlying enhanced proliferation and alterations in insulin secretion. In this aim, we propose several ex vivo comprehensive analyses to address key pathways supporting proliferation versus insulin secretion by coupling RNA sequencing techniques with stable isotope tracer-based metabolomics analyses. These studies, in combination with additional mechanistic approaches, are designed to reveal how substrate usage is altered by caloric excess to drive beta-cell mass expansion and importantly, how SGK1 inhibition limits this response to improve metabolic outcomes. Completing these Aims will reveal the critical SGK1-dependent molecular events responsible for regulating islet beta-cell changes in growth and secretory function during caloric overload, obesity, and insulin resistance. Collectively, the results of these studies are expected to inform the future design of therapies targeting cellular growth mechanisms important for diagnosing and treating metabolic diseases.

胰腺β细胞团扩增发生在肥胖和胰岛素抵抗的早期阶段。相反，糖尿病患者的胰岛β细胞数量减少，功能减弱，表明胰岛β细胞的扩增和丧失是受信号诱导调节的动态过程。利用胰岛素需求信号或产生胰岛素抵抗的外部信号，我们查询了啮齿动物和人类β细胞中与生长和增殖途径相关的诱导基因的基因表达变化。这种方法产生了血清和糖皮质激素诱导激酶1 (SGK1)，它在暴露于细胞因子、葡萄糖、糖皮质激素和脂质后迅速上调。因此，我们创建了胰腺β细胞中缺乏SGK1的小鼠，以解决一个根本性的重要问题：抑制胰岛β细胞中SGK1是否会阻止它们在热量过载和胰岛素抵抗状态下的扩张能力？我们的初步数据显示，在高脂肪喂养过程中，β细胞中的SGK1缺失限制了胰岛质量的扩大。有趣的是，在体外和体内，β细胞中的SGK1抑制增加了胰岛素分泌，从而改善了全身葡萄糖耐量。基于这些初步数据，我们假设限制β细胞增殖具有改善刺激-分泌耦合以促进胰岛素分泌的附加益处。为了验证这一总体假设，提出了以下目标。特异性目标1将研究SGK1如何调节β细胞质量以响应产生胰岛素需求的信号。我们将使用基于SGK1缺失小鼠的初步数据的体内方法，使用两种已建立的实验范式：高脂肪喂养和连续葡萄糖输注来研究β细胞增殖的早期变化。特异性目标2将研究增殖增强和胰岛素分泌改变的机制。为此，我们提出了几种体外综合分析，通过将RNA测序技术与基于稳定同位素示踪剂的代谢组学分析相结合，来解决支持增殖与胰岛素分泌的关键途径。这些研究与其他机制方法相结合，旨在揭示热量过剩如何改变底物的使用以驱动β细胞质量扩增，重要的是，SGK1抑制如何限制这种反应以改善代谢结果。完成这些目标将揭示在热量过载、肥胖和胰岛素抵抗期间，负责调节胰岛β细胞生长和分泌功能变化的关键sgk1依赖分子事件。总的来说，这些研究的结果有望为未来设计针对细胞生长机制的治疗方法提供信息，这些机制对诊断和治疗代谢性疾病很重要。

项目成果

Pioglitazone Reverses Markers of Islet Beta-Cell De-Differentiation in db/db Mice While Modulating Expression of Genes Controlling Inflammation and Browning in White Adipose Tissue from Insulin-Resistant Mice and Humans.

• DOI: 10.3390/biomedicines9091189
• 发表时间: 2021-09-10
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Collier JJ;Batdorf HM;Merrifield KL;Martin TM;White U;Ravussin E;Burk DH;Cooley CR;Karlstad MD;Burke SJ
• 通讯作者: Burke SJ

Pharmacological inhibition of lipolysis prevents adverse metabolic outcomes during glucocorticoid administration.

• DOI: 10.1016/j.molmet.2023.101751
• 发表时间: 2023-08
• 期刊: MOLECULAR METABOLISM
• 影响因子: 8.1
• 作者: Linden, Melissa A.;Burke, Susan J.;Pirzadah, Humza A.;Huang, Tai-Yu;Batdorf, Heidi M.;Mohammed, Walid K.;Jones, Katarina A.;Ghosh, Sujoy;Campagna, Shawn R.;Collier, J. Jason;Noland, Robert C.
• 通讯作者: Noland, Robert C.

The Ubiquitin Ligase SIAH2 Negatively Regulates Glucocorticoid Receptor Activity and Abundance.

• DOI: 10.3390/biomedicines9010022
• 发表时间: 2020-12-30
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Burke SJ;Taylor JL;Batdorf HM;Noland RC;Burk DH;Yu Y;Floyd ZE;Collier JJ
• 通讯作者: Collier JJ

ICAM-1 Abundance Is Increased in Pancreatic Islets of Hyperglycemic Female NOD Mice and Is Rapidly Upregulated by NF-κB in Pancreatic β-Cells.

• DOI: 10.4049/jimmunol.2200065
• 发表时间: 2022-08-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)

Stereoisomers of an Aryl Pyrazole Glucocorticoid Receptor Agonist Scaffold Elicit Differing Anti-inflammatory Responses.

芳基吡唑糖皮质激素受体激动剂支架的立体异构体引起不同的抗炎反应。

• DOI: 10.1021/acsmedchemlett.2c00299
• 发表时间: 2022
• 期刊: ACS medicinal chemistry letters
• 影响因子: 4.2
• 作者: Lato,AshleyM;Burke,SusanJ;Ducote,MaggieP;Kennedy,BrandonJ;Collier,JJason;Campagna,ShawnR
• 通讯作者: Campagna,ShawnR